Recombinant human growth hormone for the treatment of growth disorders in children: a systematic review and economic evaluation

Recombinant human growth hormone (rhGH) is licensed for short stature associated with growth hormone deficiency (GHD), Turner syndrome (TS), Prader-Willi syndrome (PWS), chronic renal insufficiency (CRI), short stature homeobox-containing gene deficiency (SHOX-D) and being born small for gestational age (SGA). To assess the clinical effectiveness and cost-effectiveness of rhGH compared with treatment strategies without rhGH for children with GHD, TS, PWS, CRI, SHOX-D and those born SGA. The systematic review used a priori methods. Key databases were searched (e.g. MEDLINE, EMBASE, NHS Economic Evaluation Database and eight others) for relevant studies from their inception to June 2009. A decision-analytical model was developed to determine cost-effectiveness in the UK. Two reviewers assessed titles and abstracts of studies identified by the search strategy, obtained the full text of relevant papers, and screened them against inclusion criteria. Data from included studies were extracted by one reviewer and checked by a second. Quality of included studies was assessed using standard criteria, applied by one reviewer and checked by a second. Clinical effectiveness studies were synthesised through a narrative review. Twenty-eight randomised controlled trials (RCTs) in 34 publications were included in the systematic review. GHD: Children in the rhGH group grew 2.7 cm/year faster than untreated children and had a statistically significantly higher height standard deviation score (HtSDS) after 1 year: -2.3 ± 0.45 versus -2.8 ± 0.45. TS: In one study, treated girls grew 9.3 cm more than untreated girls. In a study of younger children, the difference was 7.6 cm after 2 years. HtSDS values were statistically significantly higher in treated girls. PWS: Infants receiving rhGH for 1 year grew significantly taller (6.2 cm more) than those untreated. Two studies reported a statistically significant difference in HtSDS in favour of rhGH. CRI: rhGH-treated children in a 1-year study grew an average of 3.6 cm more than untreated children. HtSDS was statistically significantly higher in treated children in two studies. SGA: Criteria were amended to include children of 3+ years with no catch-up growth, with no reference to mid-parental height. Only one of the RCTs used the licensed dose; the others used higher doses. Adult height (AH) was approximately 4 cm higher in rhGH-treated patients in the one study to report this outcome, and AH-gain SDS was also statistically significantly higher in this group. Mean HtSDS was higher in treated than untreated patients in four other studies (significant in two). SHOX-D: After 2 years' treatment, children were approximately 6 cm taller than the control group and HtSDS was statistically significantly higher in treated children. The incremental cost per quality adjusted life-year (QALY) estimates of rhGH compared with no treatment were: 23,196 pounds for GHD, 39,460 pounds for TS, 135,311 pounds for PWS, 39,273 pounds for CRI, 33,079 pounds for SGA and 40,531 pounds for SHOX-D. The probability of treatment of each of the conditions being cost-effective at 30,000 pounds was: 95% for GHD, 19% for TS, 1% for PWS, 16% for CRI, 38% for SGA and 15% for SHOX-D.

The clinical effectiveness and cost-effectiveness of bariatric (weight loss) surgery for obesity: a systematic review and economic evaluation

To assess the clinical effectiveness and cost-effectiveness of bariatric surgery for obesity. Seventeen electronic databases were searched [MEDLINE; EMBASE; PreMedline In-Process & Other Non-Indexed Citations; The Cochrane Library including the Cochrane Systematic Reviews Database, Cochrane Controlled Trials Register, DARE, NHS EED and HTA databases; Web of Knowledge Science Citation Index (SCI); Web of Knowledge ISI Proceedings; PsycInfo; CRD databases; BIOSIS; and databases listing ongoing clinical trials] from inception to August 2008. Bibliographies of related papers were assessed and experts were contacted to identify additional published and unpublished references. Two reviewers independently screened titles and abstracts for eligibility. Inclusion criteria were applied to the full text using a standard form. Interventions investigated were open and laparoscopic bariatric surgical procedures in widespread current use compared with one another and with non-surgical interventions. Population comprised adult patients with body mass index (BMI) > or = 30 and young obese people. Main outcomes were at least one of the following after at least 12 months follow-up: measures of weight change; quality of life (QoL); perioperative and postoperative mortality and morbidity; change in obesity-related comorbidities; cost-effectiveness. Studies eligible for inclusion in the systematic review for comparisons of Surgery versus Surgery were RCTs. For comparisons of Surgery versus Non-surgical procedures eligible studies were RCTs, controlled clinical trials and prospective cohort studies (with a control cohort). Studies eligible for inclusion in the systematic review of cost-effectiveness were full cost-effectiveness analyses, cost-utility analyses, cost-benefit analyses and cost-consequence analyses. One reviewer performed data extraction, which was checked by two reviewers independently. Two reviewers independently applied quality assessment criteria and differences in opinion were resolved at each stage. Studies were synthesised through a narrative review with full tabulation of the results of all included studies. In the economic model the analysis was developed for three patient populations, those with BMI > or = 40; BMI > or = 30 and < 40 with Type 2 diabetes at baseline; and BMI > or = 30 and < 35. Models were applied with assumptions on costs and comorbidity.

The International Society for Bipolar Disorders (ISBD) Task Force report on the nomenclature of course and outcome in bipolar disorders

Objectives:  Via an international panel of experts, this paper attempts to document, review, interpret, and propose operational definitions used to describe the course of bipolar disorders for worldwide use, and to disseminate consensus opinion, supported by the existing literature, in order to better predict course and treatment outcomes. Methods:  Under the auspices of the International Society for Bipolar Disorders, a task force was convened to examine, report, discuss, and integrate findings from the scientific literature related to observational and clinical trial studies in order to reach consensus and propose terminology describing course and outcome in bipolar disorders. Results:  Consensus opinion was reached regarding the definition of nine terms (response, remission, recovery, relapse, recurrence, subsyndromal states, predominant polarity, switch, and functional outcome) commonly used to describe course and outcomes in bipolar disorders. Further studies are needed to validate the proposed definitions. Conclusion:  Determination and dissemination of a consensus nomenclature serve as the first step toward producing a validated and standardized system to define course and outcome in bipolar disorders in order to identify predictors of outcome and effects of treatment. The task force acknowledges that there is limited validity to the proposed terms, as for the most part they represent a consensus opinion. These definitions need to be validated in existing databases and in future studies, and the primary goals of the task force are to stimulate research on the validity of proposed concepts and further standardize the technical nomenclature.

Comparative analysis of caveolins in mouse and tammar wallaby: role in regulating mammary gland function.

Recent studies using the mouse showed an inverse correlation between the Caveolin 1 gene expression and lactation, and this was regulated by prolactin. However, current study using mammary explants from pregnant mice showed that while insulin (I), cortisol (F) and prolactin (P) resulted in maximum induction of the β-casein gene, FP and IFP resulted in the downregulation of Caveolin 1. Additionally, IF, FP and IFP resulted in the downregulation of Caveolin 2. Immunohistochemistry confirmed localisation of Caveolin 1 specific to myoepithelial cells and adipocytes. Comparative studies with the tammar wallaby showed Caveolin 1 and 2 had 70-80% homology with the mouse proteins. However, in contrast to the mouse, Caveolin 1 and 2 genes showed a significantly increased level of expression in the mammary gland during lactation. The regulation of tammar Caveolin 1 and 2 gene expression was examined in mammary explants from pregnant tammars, and no significant difference was observed either in the absence or in the presence of IFP.

Taking the sting out of darting : Risks, restraint drugs and procedures for the chemical restraint of Southern Hemisphere otariids

The need to manage otariid populations has necessitated the development of a wide range of capture methods. Chemical restraint by remote drug delivery (i.e., darting) is a highly selective method that can be used to facilitate otariid capture in a range of scenarios, when other methods may be impracticable. However, the risks associated with darting otariids are not widely known and guidelines necessary to promote and refine best practice do not exist. We review the risks associated with darting and in light of our findings, develop darting guidelines to help practitioners assess and minimize risks during capture, anesthesia and recovery. Published studies reveal that mortalities associated with darting predominantly result from complications during anesthetic maintenance (e.g., prolonged respiratory depression, apnea, or hyperthermia), rather than from complications during capture or recovery. In addition to monitoring vital signs and proper intervention, the risk of irreversible complications during anesthesia can be reduced by administering drug doses that are sufficient to enable the capture and masking of animals, after which anesthetic depth can be regulated using gas anesthesia.

The rigour of IFRS education in the USA: analysis, reflection and innovativeness

International Financial Reporting Standards (IFRS) are accepted throughout the world, particularly in the European Union, Australia, New Zealand and Canada. Emerging economies are also are aligning their practices with IFRS. Historically, the USA has been cautious about accepting IFRS. However, following acceptance of IFRS worldwide, the US Securities and Exchange Commission has recently allowed the filing of IFRS-based financial statements from foreign issuers and is presently considering the same from domestic issuers. Owing to lack of IFRS education and training in the country, concerns have been expressed about such moves of the USA towards IFRS. Following such concerns, the aim of the present study is to review previous literature on IFRS education to reflect on the present status of IFRS education in the USA. The research method includes a review of past literature on IFRS education in the Business Source Complete database from 2001 to 2012. In line with the review, this study reports that active learning approaches that stimulate critical thinking and judgement skills of students are the best methods to teach IFRS. The studies reviewed also report the lack of teaching materials, including software and technologies, to effectively teach IFRS. The only active learning strategies advocated in previous studies were the use of case studies and real life examples. Additionally, this study advocates the use of problem-based learning strategies. This study also reports the lack of research investigating students’ and educators' perceptions of available resources and approaches. Future studies are suggested in this direction, employing surveys and interviews.

Bid chimeras indicate that most BH3-only proteins can directly activate Bak and Bax, and show no preference for Bak versus Bax

The mitochondrial pathway of apoptosis is initiated by Bcl-2 homology region 3 (BH3)-only members of the Bcl-2 protein family. On upregulation or activation, certain BH3-only proteins can directly bind and activate Bak and Bax to induce conformation change, oligomerization and pore formation in mitochondria. BH3-only proteins, with the exception of Bid, are intrinsically disordered and therefore, functional studies often utilize peptides based on just their BH3 domains. However, these reagents do not possess the hydrophobic membrane targeting domains found on the native BH3-only molecule. To generate each BH3-only protein as a recombinant protein that could efficiently target mitochondria, we developed recombinant Bid chimeras in which the BH3 domain was replaced with that of other BH3-only proteins (Bim, Puma, Noxa, Bad, Bmf, Bik and Hrk). The chimeras were stable following purification, and each immunoprecipitated with full-length Bcl-xL according to the specificity reported for the related BH3 peptide. When tested for activation of Bak and Bax in mitochondrial permeabilization assays, Bid chimeras were ~1000-fold more effective than the related BH3 peptides. BH3 sequences from Bid and Bim were the strongest activators, followed by Puma, Hrk, Bmf and Bik, while Bad and Noxa were not activators. Notably, chimeras and peptides showed no apparent preference for activating Bak or Bax. In addition, within the BH3 domain, the h0 position recently found to be important for Bax activation, was important also for Bak activation. Together, our data with full-length proteins indicate that most BH3-only proteins can directly activate both Bak and Bax.

DNA methylation and the social gradient of osteoporotic fracture: a conceptual model

INTRODUCTION: Although there is a documented social gradient for osteoporosis, the underlying mechanism(s) for that gradient remain unknown. We propose a conceptual model based upon the allostatic load theory, to suggest how DNA methylation (DNAm) might underpin the social gradient in osteoporosis and fracture. We hypothesise that social disadvantage is associated with priming of inflammatory pathways mediated by epigenetic modification that leads to an enhanced state of inflammatory reactivity and oxidative stress, and thus places socially disadvantaged individuals at greater risk of osteoporotic fracture. METHODS/RESULTS: Based on a review of the literature, we present a conceptual model in which social disadvantage increases stress throughout the lifespan, and engenders a proinflammatory epigenetic signature, leading to a heightened inflammatory state that increases risk for osteoporotic fracture in disadvantaged groups that are chronically stressed. CONCLUSIONS: Our model proposes that, in addition to the direct biological effects exerted on bone by factors such as physical activity and nutrition, the recognised socially patterned risk factors for osteoporosis also act via epigenetic-mediated dysregulation of inflammation. DNAm is a dynamic modulator of gene expression with considerable relevance to the field of osteoporosis. Elucidating the extent to which this epigenetic mechanism transduces the psycho-social environment to increase the risk of osteoporotic fracture may yield novel entry points for intervention that can be used to reduce individual and population-wide risks for osteoporotic fracture. Specifically, an epigenetic evidence-base may strengthen the importance of lifestyle modification and stress reduction programs, and help to reduce health inequities across social groups. MINI ABSTRACT: Our conceptual model proposes how DNA methylation might underpin the social gradient in osteoporotic fracture. We suggest that social disadvantage is associated with priming of inflammatory signalling pathways, which is mediated by epigenetic modifications, leading to a chronically heightened inflammatory state that places disadvantaged individuals at greater risk of osteoporosis.

The extended Infant Feeding, Activity and Nutrition Trial (InFANT Extend) Program : a cluster-randomized controlled trial of an early intervention to prevent childhood obesity

BACKGROUND: Understanding how we can prevent childhood obesity in scalable and sustainable ways is imperative. Early RCT interventions focused on the first two years of life have shown promise however, differences in Body Mass Index between intervention and control groups diminish once the interventions cease. Innovative and cost-effective strategies seeking to continue to support parents to engender appropriate energy balance behaviours in young children need to be explored. METHODS/DESIGN: The Infant Feeding Activity and Nutrition Trial (InFANT) Extend Program builds on the early outcomes of the Melbourne InFANT Program. This cluster randomized controlled trial will test the efficacy of an extended (33 versus 15 month) and enhanced (use of web-based materials, and Facebook® engagement), version of the original Melbourne InFANT Program intervention in a new cohort. Outcomes at 36 months of age will be compared against the control group. DISCUSSION: This trial will provide important information regarding capacity and opportunities to maximize early childhood intervention effectiveness over the first three years of life. This study continues to build the evidence base regarding the design of cost-effective, scalable interventions to promote protective energy balance behaviors in early childhood, and in turn, promote improved child weight and health across the life course. TRIAL REGISTRATION: ACTRN12611000386932 . Registered 13 April 2011.